The present invention generally relates to anti -microbial coatings and surfaces.
Silver ion is one example of the relatively few antiseptic materials which are tolerated internally by humans at concentrations that are effective to kill microbes. Among antiseptic metal ions, silver is one of the best known. Silver is particularly useful because it is not substantially absorbed into the body. With an exceedingly long history of use, water-soluble silver salts have been used as antiseptics for hundreds of years, and are perhaps best known for disinfecting the eyes of newborn infants, thus preventing blindness. Other antiseptic metal ions include copper, zinc, mercury, tin, lead, bismuth, cadmium, chromium, and thallium. But the latter ions are less preferred than silver for internal use. The afore-mentioned metal ions are believed to exert their effects by disrupting respiration and electron transport systems upon absorption into bacterial or fungal cells.
Unless stated otherwise, the term “silver”, when used alone in this specification, means silver ion.
A preferred inorganic antimicrobial agent is an antibiotic zeolite. Suitable zeolites are disclosed in U.S. Pat. No. 4,938,955, the disclosure of which is incorporated by reference herein. Antibiotic zeolites have been prepared by replacing all or part of the ion-exchangeable ions in zeolite with ammonium ions and antibiotic metal ions, as described in U.S. Pat. Nos. 4,938,958 and 4,911,898, the disclosures of which are incorporated by reference herein. Such zeolites have been incorporated into resins, and used to make various products such as refrigerators, dishwashers, rice cookers, plastic film, chopping boards, vacuum bottles, plastic pails, garbage containers, flooring, wall paper, cloth, paint, napkins, plastic automobile parts, catheters, bicycles, pens, toys, sand, and concrete. The resins incorporating the zeolites, and the uses mentioned above, are described in one or more of the above-cited patents, and/or in U.S. Pat. Nos. 4,906,464, 4,775,585, 5,714,445, 5,697,203, 5,562,872, 5,180,585, 5,714,430, and 5,102,401, the disclosures of all of which are incorporated by reference herein. Other patents relevant to zeolites include U.S. Pat. Nos. 5,556,699, 4,911,899, and 4,923,450, the disclosures of which are also incorporated by reference herein.
Antibiotic ceramic particles useful with the present invention include zeolites, hydroxy apatite, zirconium phosphates, and other ion-exchange ceramics. Zeolites are preferred, and are described in the preferred embodiments set forth below. Hydroxy apatite particles containing antimicrobial metals are described in U.S. Pat. No. 5,009,898, the disclosure of which is incorporated by reference herein. Zirconium phosphates containing antimicrobial metals are described in U.S. Pat. Nos. 5,296,238, 5,441,717, and 5,405,644, the disclosures of which are also incorporated by reference herein.
Either natural zeolites or synthetic zeolites can be used to make the antibiotic zeolites used in the present invention. Zeolite is an aluminosilicate having a three-dimensional skeletal structure that is represented by the formula:XM2/nO—Al2O3—YSiO2—ZH2Owhere M represents an ion-exchangeable ion, generally a monovalent or divalent metal ion, n represents the atomic valency of the metal ion, X and Y represent coefficients of metal oxide and silica respectively, and Z represents the number of water of crystallization. Examples of such zeolites include A-type zeolites, X-type zeolites, Y-type zeolites, T-type zeolites, high-silica zeolites, sodalite, mordenite, analcite, clinoptilolite, chabazite, and erionite. The present invention is not restricted to use of these specific zeolites.
The ion-exchange capacities of these zeolites are as follows: A-type zeolite=7 meq/g; X-type zeolite=6.4 meq/g; Y-type zeolite=5 meq/g; T-type zeolite=3.4 meq/g; sodalite=11.5 meq/g; mordenite=2.6 meq/g; analcite=5 meq/g; clinoptilolite=2.6 meq/g; chabazite=5 meq/g; and erionite=3.8 meq/g. These ion-exchange capacities are sufficient for the zeolites to undergo ion-exchange with ammonium and antibiotic metal ions.
The specific surface area of preferred zeolite particles is preferably at least 150 m2/g (anhydrous zeolite as standard) and the SiO2/Al2O3 mol ratio in the zeolite composition is preferably less than 14, more preferably less than 11.
The antibiotic metal ions used in the antibiotic zeolites should be retained on the zeolite particles through an ion-exchange reaction. Antibiotic metal ions which are adsorbed or attached without an ion-exchange reaction exhibit a decreased bactericidal effect and their antibiotic effect is not long-lasting. Nevertheless, it is advantageous for imparting quick antimicrobial action to maintain a sufficient amount of surface adsorbed metal ion.
During the ion-exchange process, if the concentration of metal ions in the vicinity of the zeolite surface is high, there is a tendency for the antimicrobial metal ions (cations) to be converted into their oxides, hydroxides, basic salts, etc., which deposit in the micropores or on the surfaces of the zeolite. This deposition may adversely affect the bactericidal properties of the ion-exchanged zeolite.
In an embodiment of the antibiotic zeolites, a relatively low degree of ion exchange is employed to obtain superior bactericidal properties. It is believed to be required that at least a portion of the zeolite particles retain metal ions having bactericidal properties at ion-exchangeable sites of the zeolite in an amount less than the ion-exchange saturation capacity of the zeolite. In one embodiment, the zeolite employed in the present invention retains antimicrobial metal ions in an amount up to 41% of the theoretical ion-exchange capacity of the zeolite. Such ion-exchanged zeolite with a relatively low degree of ion-exchange may be prepared by performing ion-exchange using a metal ion solution having a low concentration as compared with solutions conventionally used for ion exchange.
The antibiotic metal ion is preferably present in the range of from about 0.1 to 20% (by weight) of the zeolite. In one embodiment, the zeolite contains from 0.1 to 20% (by weight) of silver ions and from 0.1 to 20% (by weight) of copper or zinc ions. Although ammonium ion can be contained in the zeolite at a concentration of about 20% or less (by weight) of the zeolite, it is desirable to limit the content of the ammonium ions to from 0.5 to 15% (by weight), preferably 1.5 to 5%. The percent by weight described herein is determined for materials dried at temperatures such as 110° C., 250° C. or 550° C. as this is the temperature employed for the preferred post-manufacturing drying process.
A preferred antibiotic zeolite is type A zeolite containing either a combination of ion-exchanged silver, zinc, and ammonium or silver and ammonium. One such zeolite is manufactured by Shinegawa, Inc., under the product number AW-10N and consists of 0.6% (by weight) of silver ion-exchanged in Type A zeolite particles having a diameter of about 2.5 microns. Another formulation, sold under the product number AJ-10N, consists of about 2% (by weight) silver ion-exchanged in Type A zeolite particles having a diameter of about 2.5 microns. Another formulation, sold under the product number AW-80, contains 0.6% (by weight) of silver ion-exchanged in Type A zeolite particles having a diameter of about 1.0 microns. Another formulation, sold under the product number AJ-80N, consists of about 2% (by weight) silver ion-exchanged in Type A zeolite particles having a diameter of about 1.0 microns. These zeolites preferably contain between about 0.5% and 2.5%, by weight, of ion-exchanged ammonium.
The zeolites are often obtained in master batches of low density polyethylene, polypropylene, or polystyrene, containing 20% (by weight) of the zeolite.
The antibiotic properties of the antibiotic zeolite particles of the invention may be assayed while in aqueous formulations using conventional assay techniques, including, for example, determining the minimum growth inhibitory concentration (MIC) with respect to a variety of bacteria, eumycetes, and yeast. In such a test, one may use any of the following bacteria: Bacillus cereus varmycoides, Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Streptococcus faecalis, Aspergillus niger, Aureobasidium pullulans, Chaetomium globosum, Gliocladium virens, Penicillum funiculosum, Candida albicans, and Saccharomyces cerevisiae. 
The assay for determining MIC can be carried out by smearing a solution containing bacteria for inoculation onto a plate culture medium to which a test sample of the encapsulated antibiotic zeolite particles is added in a particular concentration, followed by incubation and culturing of the plate. The MIC is defined as a minimum concentration thereof required for inhibiting the growth of each bacteria.
A number of strategies have been used to develop anti-infective surfaces for medical devices. Various approaches are described in J. A. Chinn, M. A. Moore, G. Cook and J. W. Costerton, “Anti-infective medical device strategies”: Surfaces in Biomaterials Symposium, 1998, pp. 105-109, and in A. E. Khoury, “The pathophysiology and management of device related infections”: Surfaces in Biomaterials Symposium, 1998, pp. 99-103.
Among the most promising techniques are those that combine different mechanisms of activity, such as the use of materials inherently resistant to bacterial attachment, and the inclusion of anti-microbial agents in the structure or device surface. It is an object of the invention to provide such an advantageous anti-infective coating by combining an inherent resistance to microbial attachment with an antiseptic activity.
Medical devices coated with a hyaluronate surface layer are well known to exhibit a marked reduction or absence of cellular attachment and fouling by bacteria, as for example is described in D. Hoekstra, “Hyaluronan-modified surfaces for medical devices”: Medical Device and Diagnostic Industry”, February 1999, and “Evaluation of interfacial properties of hyaluronan coated poly(methylmethacrylate) intraocular lenses”, Journal of Biomaterials Science, Polymer Edition, vol. 11, No. 9, pp. 961-978 (2000). These hyaluronate coatings also confer a high lubricity to the device surface. Hyaluronate is a negatively-charged mucopolysaccharide, present in virtually all animal life forms, that also confers high lubricity when used to coat medical devices. It nonetheless has proved difficult to modify these coatings to obtain effective, sustained anti-microbial activity without interfering with the coating chemistry itself or without modifying the properties of the final, cured hyaluronate coating. Silver ion has been particularly difficult to incorporate into hyaluronan coatings.
Examples of patents showing medical devices, and other devices, having a biocompatible coating, are U.S. Pat. Nos. 4,657,820, 4,663,233, 4,722,867, 4,801,475, 4,959,074, 5,023,114, 5,037,677, 5,789,571, 5,840,046, 6,042,876, and 6,187,369, the disclosures of which are incorporated by reference herein.
For example, the family of bi-laminar, biocompatible coatings that is commercially available under the trademark HYDAK (HYDAK is a trademark of Biocoat Incorporated, of Ft. Washington, Pa.) provides several different acrylic base coat polymers that provide adhesion to the substrate, together with a topcoat of sodium hyaluronate that is covalently grafted to the base coat. When simple, broad-spectrum anti-microbial agents like silver salts are included in the coating solutions, the silver ion interferes with the formation of the base coat film itself, as well as binding to the hyaluronate carboxylate and modifying the lubricity of the coated surface.
Nonetheless, if silver ion is exchanged onto the negatively charged surface of a hyaluronate coating, this antiseptic silver will be released into the bodily fluids upon contact with them. The silver store is rapidly exhausted, however. Thus, it is an object of the invention to provide an antiseptic silver-based coating with a more sustained release of silver that prolongs the effectiveness of the antiseptic activity.
Antibiotics added to a coated medical device, for example, by soaking the device in an antibiotic solution just before insertion into the body, are released rapidly and lost from the vicinity of the device in a matter of hours. This transient antibiotic presence may cause an immediate reduction of contaminating microbes in the vicinity of the device insertion, but the benefit is usually lost in hours, well before the withdrawal of typical coated medical devices such as urinary or central venous catheters. Any bacteria that survive this initial antibiotic release are then able to grow and cause harm. Moreover, bacteria or other pathogens often exhibit resistance to antibiotics, in contrast to antiseptics.
It therefore would be a significant advance in the art to provide a means and method for incorporating a source of anti-microbial silver ion in a bi-laminar, biocompatible coating composition of the above-described type, without the aforementioned adverse effects on base coat formation and surface lubricity.